DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10; rule 13)

“SUBSTANTIALLY PURE VILDAGLIPTIN AND A PROCESS THEREOF”

HIKAL LIMITED, an Indian Company, of 3A& 3B, International Biotech Park, Hinjewadi, Pune – 411057, Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to substantially pure Vildagliptin having an imine N-oxide impurity not more than 0.15% and a process for the preparation thereof. The invention further relates to a process for the preparation of substantially pure Vildagliptin using an antioxidant followed by purification.

BACKGROUND OF THE INVENTION

Vildagliptin is an oral antihyperglycemic reagent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin is chemically known as (S)-1-[N-(3-hydroxy-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile and marketed under the brand name Galvus. Vildagliptin exists in (2S) and (2R) enantiomers, but the desired biological activity is shown by (2S) enantiomer. Vildagliptin of formula (I) and a process for its preparation is disclosed in US Patent No.6,166,063A.

The US patent application US 2008/0167479 A1, discloses the preparation and purification of Vildagliptin which involve:i) reacting L-prolinamide with 2-chloroacetyl chloride in presence of iso-propyl acetate and dimethyl formamide (DMF); ii) dehydration of amide with cyanuric chloride and crystallization from isopropyl alcohol resulting in 66% yield; iii) condensing with 3-Amino -1-hydroxy adamantane in presence of inorganic base such as caesium carbonate, catalyst, in presence of costly, explosive ethereal solvent; and iv) purifying using one or more solvents to obtain pure Vildagliptin with low overall yield 60-70%.

The patent application IN 2010/CHE/225, discloses the process for preparation and purification of Vildagliptin which involve: i) reacting L-prolinamide with 2-chloroacetyl chloride in presence of alkali metal carbonate or bicarbonates; ii) dehydration of amide with corrosive trifluoroacetic anhydride or oxalyl chloride; iii) condensing with 3-amino-1-hydroxy adamantane in presence of alkali metal carbonates/bicarbonates, in costly, flammable ether solvent;and iv) purifying using ester and alcoholic solvents to obtain pure Vildagliptin with low yield 60%.

The patent application IN 2012/MUM/2214, discloses the process for preparation and purification of Vildagliptin which involve: i) protection of L-prolinamide in presence of inorganic base; ii) dehydration of amide; iii) deprotection and reaction with 2-chloro acetyl chloride in presence of organic base; iv) condensation with 3-Amino -1-hydroxy adamantane in presence of inorganic base, in solvent to obtain crude Vildagliptin; and v) purification in presence of acid and base to obtain pure Vildagliptin with purity 99.8%.

The existing processes are suffered with one or more disadvantages for example: i) protection and deprotection step; ii) costly, corrosive reagent and explosive solvents; iii) use of multiple solvents for intermediate purification; and iv) acid, base purification for isolation of pure Vildagliptin. Moreover, none of above prior arts disclose Vildagliptin process impurities including the formation of imine N-oxide vildagliptin impurity. The process requires multiple purification steps for reduction or removal of impurities, which reduces overall yield and increase production cost.

Thus, there is a need for substantially pure Vildagliptin particularly with a process to control the impurity formation and further purification. To overcome the limitations of the existing process, the inventors have come-up with an improved process to obtain substantially pure Vildagliptin having imine N-oxide impurity not more than 0.15%.

SUMMARY OF THE INVENTION

In one aspect, the invention provides substantially pure Vildagliptin of formula (I) having imine N-oxide impurity not more than 0.15%.

In another aspect, the invention provides an improved process for the preparation of substantially pure Vildagliptin of formula (I) using suitable antioxidant followed by purification step.

In another aspect, the invention provides an improved process for the preparation of substantially pure Vildagliptin of formula (I) having imine N-oxide impurity not more than 0.15% using suitable antioxidant followed by purification step.

In another aspect, the present invention relates to a process for the preparation of substantially pure vildagliptin of formula (I) having purity more than 99.5% and imine N-oxide impurity less than 0.15% by HPLC.

In another aspect, the present invention relates to a process for the preparation of substantially pure Vildagliptin of formula (I) which comprises the steps of:

(a) condensing a compound of formula (VI) where X is chloro, bromo with 1-amino-adamantane-3-ol of formula (VII) in presence of a base, an antioxidant, in a suitable solvent with or without catalyst to obtain crude Vildagliptin having imine N-oxide impurity formula (VIII);

(b) purifying crude Vildagliptin in a solvent to obtain substantially pure Vildagliptin of formula (I).

In one embodiment, the substantially pure Vildagliptin contains purity more than 95% and N-oxide impurity formula (VIII) NMT 0.15% by HPLC.

In one embodiment, the substantially pure Vildagliptin contains purity more than 98% and N-oxide impurity formula (VIII) NMT 0.15% by HPLC.

In one embodiment of the present invention, wherein the compound of formula (VI) is prepared by sequential transformations comprising the steps of:
a) reacting L-proline (II) with a thionyl chloride in presence of an alcoholic solvent to obtain formula (III);
b) reacting formula (III) with an ammonia gas in presence of solvent(s) to obtain L-Prolinamide of formula (IV);
c) reacting formula (IV) with a Chloroacetyl chloride or bromo acetyl chloride in presence of a solvent to obtain compound (V);
d) reacting formula (V) with a dehydrating agent to obtain formula (VI).

In one embodiment of the present invention, wherein the purification of crude Vildagliptin to obtain substantially pure Vildagliptin of formula (I) comprising steps of:
a) dissolving crude Vildagliptin in a solvent;
b) adding an antioxidant;
c) cooling to isolate the solid; and
d) drying.

In one embodiment of the present invention, wherein the crude Vildagliptin contains(2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile, 3-Amino-adamantan-1-ol , N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl-L Prolinamide, (2S,2'S)-1,1'-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino] bis(1-oxo-2,1-ethanediyl)]bis-2-Pyrrolidinecarbonitrile, and (Z)-2-((S)-2-cyanopyrrolidin-1-yl)-N-(3-hydroxyadamantan-1-yl)-2-oxoethan-1-imine oxide impurities.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described more in details hereinafter. The invention is embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term “imine N-oxide impurity” of formula (VIII) used herein, refers to (Z)-2-((S)-2-cyanopyrrolidin-1-yl)-N-(3-hydroxyadamantan-1-yl)-2-oxoethan-1-imine oxide.

In an embodiment of the present invention, wherein the imine N-oxide impurity formula (VIII) is characterized using Fourier-transform infrared spectroscopy (FTIR), on Nicolet 6700 FTIR spectrometer with a NXR FT Raman Module and the samples dispersed in KBr pellets with characteristic peaks values 3409, 3291, 1642, and 2237cm-1.

In an embodiment of the present invention, wherein the imine N-oxide impurity of formula (VIII) is characterized by 1H NMR (DMSO, 400 MHz): 1.48-1.56(6H, m), 1.87-1.99(8H, m), 2.11-2.27 (4H, m), 3.38-3.57, 4.78-5.03, 7.46-7.62 (5H, m, m, s).

In an embodiment of the present invention, wherein the imine N-oxide impurity of formula (VIII) is characterized by 13C NMR (DMSO, 400 MHz): 24.35,29.62, 30.21, 34.15, 38.89, 43.54, 44.43, 45.82, 47.62, 67.88, 72.90, 118.81, 124.66, and 161.14 ppm.

In an embodiment of the present invention, wherein the imine N-oxide impurity of formula (VIII) is characterized by MSSpectral data is [M+H]= 318which corresponding to a molecular formula C17H23N3O3.

The term substantially pure used herein, refers to the purity of substantially pure Vildagliptin of formula (I) is NLT 97%, preferably NLT 98%, having imine N-oxide impurity formula (VIII) NMT0.15% and total impurities NMT 3.0% by HPLC.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In an embodiment of the present invention wherein the process for the preparation of substantially pure Vildagliptin of formula (I) is illustrated in the following synthetic scheme.
Scheme 1:

In an embodiment of the present invention, wherein the compound of formula (VII) is prepared by reacting amantadine hydrochloride with nitrating mixture and isolating compound by maintaining basic pH (>12.5) and extracting using mixture of solvent such as alcoholic solvent (n-butanol) and hydrocarbon solvent (toluene).

In an embodiment of the present invention, wherein the condensation reaction in step (a) is carried out in presence or absence of base and a catalyst.

In an embodiment of the present invention, wherein the base in step (a) is inorganic base which is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bi carbonate , potassium carbonate (K2CO3), Sodium carbonate (Na2CO3) , Potassium bicarbonate, Caesium carbonate, Calcium carbonate and the like.

In an embodiment of the present invention, wherein the catalyst in step (a) is selected from potassium iodide (KI), Sodium metabisulfite (Na2S2O5), Sodium iodide (NaI), sodium bromide (NaBr), Potassium bromide (KBr), Lithium bromide (LiBr) and the like.

In an embodiment of the present invention, wherein the antioxidant is selected from Butylated hydroxy toluene (BHT), Sodium metabisulfite (Na2S2O5), Ascorbic acid, Uric acid, Glutathione, preferably Butylated hydroxy toluene (BHT).

In an embodiment of the present invention, wherein the solvent used in step (a) is polar aprotic solvents is selected from group consisting of dimethyl formamide (DMF), acetonitrile (ACN), acetone, dimethyl sulfoxide (DMSO), hexamethyl phosphoric triamide (HMPT); preferably acetonitrile.

In an embodiment of the present invention, wherein the process for the preparation of compound of formula (VI) is illustrated in the following synthetic scheme:

Scheme 2:

In an embodiment of the present invention, wherein the compounds of formula (III), (IV), and (V) is not isolated, which makes present process economic.

In an embodiment of the present invention, wherein the preparation of compound (III) is obtained by reacting compound of formula (II) with thionyl chloride and an alcoholic solvent, where the alcoholic solvent is selected from methanol, ethanol, isopropanol and the like, preferably methanol.

In an embodiment of the present invention, wherein the preparation of compound (IV) is obtained by reacting compound of formula (III) with an ammonia gas and solvent where the solvent is selected from methanol, ethanol, isopropanol, hexane, toluene, cyclohexane, preferably in combination of methanol and toluene.

In an embodiment of the present invention, wherein the preparation of compound(V) is obtained by reacting compound of formula (IV) with Chloroacetic chloride or bromo acetyl chloride in presence of solvent, where the solvent is selected from the group consisting of a polar aprotic solvent, chlorinated solvent, ketonic solvent.

In an embodiment of the present invention, wherein the polar aprotic solvent is selected from group consisting of dimethyl formamide (DMF), acetonitrile (ACN), acetone, dimethyl sulphoxide (DMSO), hexamethyl phosphoric triamide (HMPT), acetone and the like.

In an embodiment of the present invention, wherein the chlorinated solvent is selected from group consisting of dichloromethane (DCM), dichloroethane (DCE), chloroform (CHCl3), carbon tetrachloride (CCl4) and the like.

In an embodiment of the present invention, wherein the ketonic solvent is selected from group consisting of acetone, methyl ethyl ketone (MEK), Methyl Iso Butyl Ketone, Methyl Amyl Ketone and the like.

In an embodiment of the present invention, wherein the solvent used for the preparation of compound (V) is preferably a combination of dimethyl formamide (DMF) and dichloromethane (DCM).

In an embodiment of the present invention, wherein the preparation of compound (VI) is obtained by reacting compound of formula (V) with dehydrating agent in presence of solvent; where the dehydrating agent is selected from Cyanuric Chloride, oxalyl chloride, trifluoroacetic anhydride, (Chloromethylene) dimethylliminium chloride (Vilsmeier reagent), Thionyl chloride (SOCl2) and Phosphoryl chloride (POCl3), preferably Cyanuric chloride;and the solvent is selected from dimethyl acetamide (DMA), DMF, DCM, dioxane, ethyl acetate, preferablyDCM.

In an embodiment of the present invention, wherein crude Vildagliptin used in purification step comprising impurities of; (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile, 3-amino-adamantan-1-ol, N-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)glycyl-L Prolinamide, (2S,2'S)-1,1'-[[(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)imino] bis(1-oxo-2,1-ethanediyl)]bis-2 Pyrrolidinecarbonitrile,(Z)-2-((S)-2-cyanopyrrolidin-1-yl)-N-(3-hydroxyadamantan-1-yl)-2-oxoethan-1-imine oxide (VIII).

In an embodiment of the present invention, wherein crude vildagliptin contains total impurities NMT 3% and N- imine oxide impurity NMT 0.15% by HPLC.

In an embodiment of the present invention, wherein the solvent used in purification of crude vildagliptin is polar aprotic solvent which is selected from acetone, acetonitrile and the like.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL

Example 1: Preparation of 1-amino adamantane-3-ol.
In an RBF containing concentrated sulfuric acid (100 mL) an Amantadine hydrochloride (100 g) was added at room temperature (rt) and stirred for 30 min. To this reaction solution the nitrating mixture [(concentrated sulfuric acid (200mL) and nitric acid (100mL)] was added slowly at 20°C to 30°C. The temperature of reaction mixture was raised to 30°C to 40°Cand stirred for 10-15 hours. Ensure the reaction completion by GC. The reaction mixture was cooled to 20°C to 30°C. The reaction mixture was quenched by adding into aqueous solution of sodium hydroxide and maintaining the pH of reaction solution > 12.5. To the reaction solution a solvent mixture [n-Butanol (150 mL) and toluene (450 mL)] was added and stirred for 30 min. at room temperature. The organic layer separated, and water was removed by azeotropic distillation. To the organic layer activated carbon (1.0g) was added and stirred for 15-20 min at 30°C to 40°C. The organic layer was filtered, washed with toluene and solvent was removed under vacuum. To this reaction mass a solvent mixture [Toluene (300 mL) and Methanol (40 mL) was added and heated to 60°C to 70°C till clear solution observed. The reaction solution was slowly cooled up to 0°C. The precipitated solid was stirred for 15-30 min at 0°C to 5°C. The solid was filtered, washed with toluene and dried for 5 to 7 hours 55°C to 65°C to obtain 1-amino adamantane-3-ol (Yield -67g, 75.2%, Purity by GC >98%).

Example 2: Preparation of (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile starting from L-proline.

In an RBF methanol (600 mL), L-Proline (100 g) was added at rt and cooled to cooled to 0°C to 10. To this reaction solution thionyl chloride (124 g) was added for 2-3 h. The reaction mixture temperature was increases to 20°C to 30°C and stirred for 2-4 h. The solvent was removed by distillation below 50°C and methanol (600mL) was added and further cooled to 15°C to 20°C. In an autoclave a reaction solution was added, and ammonia gas was purged at 20°C to 35°C for 4-6 h. The solvent was removed from the reaction mixture and DMF (280mL) was added at 30°C to 40°C. The reaction mixture was stirred for 1-2 h at 30°C to 40°C and filtered. The filtrate containing L-Prolinamide was added dropwise into a cold solution of chloroacetylchloride (147 g) and dichloromethane (200mL) at 0°C to 5°C. The reaction mixture was stirred for 2-3 h at 20°C to 35°C. The completion of reaction is ensured by HPLC. The reaction mixture was cooled to 0°C to 5°C and cyanuric chloride (64.6 g) was added lot wise. The reaction mixture temperature was raised to 35°C to 45°C and stirred for 4-5 hours. Ensure the reaction completion by HPLC. The reaction mixture was quenched using water at 0°C to 10°C. The reaction mass temperature was allowed to raise to rt and Dichloromethane (400 mL) was added. The reaction mixture was stirred for 30 min at 20°C to 30°C.The organic layer was separated, pH adjusted between 7-10 using aq. sodium carbonate. The organic layer separated was concentrated and further swapping it with isopropyl alcohol. The reaction mass was cooled to 30°C to 40°C and seeded with (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile (purity 99.1%). The reaction mixture was further cooled to -5°C to 5°C and stirred for 1-2 hours. The solid was filtered, washed with isopropyl alcohol and dried for 6 to 7 hours to obtain (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile (Yield –91 g, overall yield61%, Purity by HPLC –99.24%).

Example 3: Preparation of (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile starting from L-Prolinamide.

In an RBF chloroacetylchloride (108, 76 g) and dichloromethane (200 mL) were charged at room temperature (rt) and cooled to 0 °C to 5 °C. In another RBF, dimethylformamide (280 mL) and L-Prolinamide (100 g) were added and stirred for 1-2 hours at rt. The L-Prolinamide solution was added into a cold solution of chloroacetyl chloride at 0 °C to 5 °C. The reaction mixture was stirred at rt and stirred for 2-3 hours. Ensure the reaction completion by HPLC. The reaction mixture was cooled to 0 °C to 5 °C and cyanuric chloride (64.6 g,) was added lot wise. The reaction mixture temperature was raised to 35 °C to 45 °C and stirred for 4-5 hours. Ensure the reaction completion by HPLC for the formation of compound of formula (IV). The reaction mixture was quenched using water at 0 °C to 10 °C. The reaction mass was allowed to rt and dichloromethane was added. The organic layer was separated, pH adjusted between 7-10 using aq. sodium carbonate. The organic layer separated was concentrated and further swapping it with isopropyl alcohol. The reaction mass was cooled to 30 °C to 40 °C and seeded with (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile (Purity >99%). The reaction mixture was further cooled to -5 °C to 5 °C and stirred for 1-2 hours. The solid was filtered, washed with isopropyl alcohol and dried for 6 to 7 hours to obtain (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile (Yield – 123.7g, 82%, Purity by HPLC – >99%).

Example 4: Preparation of crude Vildagliptin.
In an RBF, acetonitrile (600 mL), potassium carbonate (160.09g), potassium Iodide (5.76 g) and 1-amino adamantane-3-ol (203.37 g) were added at rt. To the reaction mixture, a solution of (2S)-1-(chloroacetyl)-2-Pyrrolidinecarbonitrile (200g,>99% purity) in acetonitrile (400 mL) was added dropwise for 1-2 hours and stirred for 6-8 hours at rt. The reaction completion was ensured by HPLC. To the reaction mixture, sodium metabisulphite (6.6 g) and butylated hydroxy toluene (2.0 g) were added at rt. The reaction mixture temperature was raised to 60°C to 70°C and stirred for 0.5 to 1.0 hour. The reaction mixture was filtered and washed with acetonitrile. The completion of reaction and the formation of crude Vildagliptin was ensured by HPLC. The clear organic solution was concentrated under vacuum to minimum stirrable volume. The reaction mixture was slowly cooled to -10°C to 0°C and stirred for 1-2 hours. The solid was filtered, washed with cold acetonitrile and dried for 1-2 hours to obtain Crude Vildagliptin (Yield – 272g, 77.4%, Purity by HPLC ~97%,(Z)-2-((S)-2-cyanopyrrolidin-1-yl)-N-(3-hydroxyadamantan-1-yl)-2-oxoethan-1-imine oxide impurity is less than 0.15% and total impurities less than 3.0% by HPLC).

Example 5: Preparation of substantially pure Vildagliptin(I)
In a dry RBF a containing acetone(506.25 mL) acetonitrile (506.25 mL) acrude Vildagliptin (225.0g, ~97%) was added at rt. The butylated hydroxy toluene (2.25 g) was added to above mixture and heated to 60°C to 70°C. The activated carbon (5.62g) was added and stirred for 15 to 20 min. The reaction mixture was filtered, and the clear solution was slowly cooled to -10°C to 0°C. The precipitated solid was stirred for 2-3 hours at -10°C to 0°C. The solid was filtered, washed with cold acetone and dried for 5-6 hours to obtain substantially pure Vildagliptin (Yield- 203g, 91%, Purity by HPLC-99.5%, Compound (IV) : NMT 0.15%, Dialkylated impurity: NMT 0.15%, Vildamide impurity:NMT 0.15%, Vildagliptin imine N-Oxide impurity: NMT 0.15%, R-isomer Limit: NMT 0.15%], SMUI Limit: NMT 0.10% and Total Impurity Limit: NMT0.50 %).
,CLAIMS:WE CLAIM:

1. A substantially pure Vildagliptin of formula (I), having purity greater than 98%, containing the imine N-oxide impurity (VIII) not more than 0.15%.

2. A process for the preparation of substantially pure Vildagliptin of formula (I) having imine N-oxide impurity not more than 0.15% comprising the steps of:
a) condensing a compound of formula (VI) where X is chloro, bromo with 1-amino-adamantane-3-ol of formula (VII) in presence of base, an antioxidant, in solvent with or without catalyst to obtain crude Vildagliptin having imine N-oxide impurity formula (VIII);

b) purifying crude Vildagliptin in solvent to obtain substantially pure Vildagliptin of formula (I).

3. The process as claimed in claim 2, wherein the compound of formula (VI) is prepared by sequential transformations comprising the steps of:
i. reacting L-proline (II) with a thionyl chloride in presence of an alcoholic solvent to obtain formula (III);
ii. reacting formula (III) with an ammonia gas in presence of solvent(s) to obtain L-prolinamide of formula (IV);
iii. reacting formula (IV) with a chloroacetyl chloride or bromo acetyl chloride in presence of a solvent to obtain compound (V);
iv. reacting formula (V) with a dehydrating agent to obtain formula (VI).

4. The process as claimed in claim 2, wherein the purification of crude Vildagliptin to obtain substantially pure Vildagliptin of formula (I) comprising steps of:
(a) dissolving crude Vildagliptin in solvent;
(b) adding an antioxidant;
(c) cooling to isolate the solid; and
(d) drying.

5. The “imine N-oxide impurity” of formula (VIII).

6. The process as claimed in claim 2, wherein base is inorganic base which is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium bicarbonate, caesium carbonate, and calcium carbonate.

7. The process as claimed in claim 2, wherein antioxidant is selected from Butylated hydroxy toluene (BHT), sodium metabisulfite (Na2S2O5), ascorbic acid, uric acid, and glutathione; and catalyst is selected from potassium iodide (KI), sodium metabisulfite (Na2S2O5), sodium iodide (NaI), sodium bromide (NaBr), potassium bromide (KBr), and lithium bromide (LiBr).

8. The process as claimed in claim 2, wherein solvent used for preparation of crude Vildagliptin is polar aprotic solvents which is selected from dimethyl formamide (DMF), acetonitrile (ACN), acetone, dimethyl sulfoxide (DMSO), and hexamethyl phosphoric triamide (HMPT); and the solvent used for purification of crude vildagliptin is polar aprotic solvent which is selected from acetone and acetonitrile(ACN).

9. The process as claimed in claim 3, wherein solvent used in
a. step (i) is selected from methanol, ethanol, isopropanol;
b. step (ii) is selected from methanol, ethanol, isopropanol, hexane, toluene, cyclohexane, or in combination of methanol and toluene;
c. step (iii) is polar aprotic solvent selected from dimethyl formamide (DMF), acetonitrile (ACN), acetone, dimethyl sulphoxide (DMSO), hexamethyl phosphoric triamide (HMPT); chlorinated solvent selected from dichloromethane (DCM), dichloroethane (DCE), chloroform (CHCl3), carbon tetrachloride (CCl4); and ketonic solvent selected from acetone, methyl ethyl ketone (MEK), methyl iso butyl ketone, methyl amyl ketone; and
d. step (iv) is selected from dimethyl acetamide, dimethyl formamide, dichloromethane, dioxane and ethyl acetate.

10. The process as claimed in claim 3, wherein dehydrating agent is selected from cyanuric chloride, oxalyl chloride, trifluoroacetic anhydride, (chloromethylene) dimethylliminium chloride (Vilsmeier reagent), thionyl chloride (SOCl2) and phosphoryl chloride (POCl3).