DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“AN IMPROVED PROCESS FOR PREPARATION OF 2-AMINO-5-CHLORO-N-3-DIMETHYL BENZAMIDE”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500078, Telangana, 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 an improved process for preparation of 2-amino-5-chloro-N-3-dimethylbenzamide of Formula IV, an intermediate for preparation of chlorantraniliprole or a salt thereof.

BACKGROUND OF THE INVENTION

Chlorantraniliprole is a class of anthranilic-diamide insecticide derivative compounds and is chemically known as 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-1-(3-chloro-2-pyridine-2-yl)-1H-pyrazole-5-carboxamide, it has the following structure:

Chlorantraniliprole

Chlorantraniliprole is being developed world-wide by DuPont belonging to a new class of selective insecticides featuring a novel mode of action to control a range of pests belonging to the order Lepidoptera and some other Coleoptera, Diptera and Isoptera species.

PCT application Number: 2006/062978 (“the ‘978 publication”) discloses a process for preparation of compound of Formula IV, as follows:

Compound of Formula IV is the key intermediate and main cost contributor in the preparation of chlorantraniliprole. The ‘978 application disclosed preparation of compound of Formula IV in three stage process from 2-amino-3-methyl benzoic acid of Formula I and the process involves isolation of intermediate products of Formula II and Formula III as solid, which makes the process lengthy as it involves multiple steps of solvent extractions, isolation and drying steps and this leads to low yield of the Formula IV from the starting compound of Formula I. The ‘978 process also involves use of hydrogen peroxide in oxy-chlorination, which is not viable on large scale manufacturing as it extremely shock-sensitive explosives and require special care while handling.

Further other known literatures for ex: CN103539694B, CN111134128A, CN103109816B and Nongyao (2013), 52(11), 793-795, 811discloses preparation of this compound of Formula IV but all the literatures involves the same processing strategies, isolation of intermediates as mentioned under the ‘978 publication.

Chlorantraniliprole is one of the important insecticide available in the market. As all the reported processes involves isolation of each intermediate products of Formula II and Formula III as solid in the preparation of Formula IV, which involves increasing the reactor occupancyand additional process steps such as use of multiple solvent systems for each stage, isolation of each stage by filtration, drying and testing of each intermediate; hence, the reported processes requires excess reactor occupancy and excess manufacturing time and this creates extra burden to the final cost of the material. As disclosed above, compound of Formula IV is the key cost contributor in the preparation of chlorantraniliprole and to reduce the manufacturing cost of the chlorantraniliprole it is desirable to reduce the manufacturing cost of the intermediates involved in the process.

Hence, it’s important to develop a simple and cost effective improved process for preparation of pure chlorantraniliprole or its intermediates with high yield, which is readily amenable to large scale production and free from its impurities.

The main object of the present invention is to provide a simple, cost effective, high yield process for the preparation of compound of Formula IV with avoiding the aforementioned problems. Further, the present invention relates to conversion of the compound of Formula IV to chlorantraniliprole or a salt thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for preparation of compound of Formula IV. Further, the present invention provides an improved process for preparation of compound of chlorantraniliprole through preparing the compound of Formula IV.

In accordance with one embodiment, the present invention provides an improved process for preparation of compound of Formula IV, comprising:

Formula IV

a) reacting a compound of Formula I with a phosgene or its derivative and a suitable base in a suitable solvent to obtain a compound of Formula II,

Formula I Formula II
b) reacting the compound of Formula II with a source of monomethyl amine to obtain a compound of Formula III, and

Formula III

c) reacting the compound of Formula III with a source of chloride to obtain a compound of Formula IV; wherein the step a) to c) are carried out in one-pot reaction without isolating the intermediate compound of Formula II and Formula III as solid.

In accordance another embodiment, the present invention provides an improved process for preparation of compound of Formula IV, comprising:
a) reacting a compound of Formula I with a phosgene or its derivative and a suitable inorganic base in a suitable solvent to obtain a compound of Formula II,
b) reacting the compound of Formula II with a source of monomethyl amine to obtain a compound of Formula III, and
c) reacting the compound of Formula III with a source of chloride to obtain a compound of Formula IV; wherein the step a) to c) are carried out in one-pot reaction without isolating the intermediate compound of Formula II and Formula III as solid.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula IV, comprising:
a) reacting a compound of Formula I with a phosgene or its derivative and a suitable base in a suitable solvent to obtain a solution of compound of Formula II,
b) adding a source of monomethyl amine to the solution of compound of Formula II to obtain a solution of compound of Formula III,
c) adding a source of chloride to the solution of compound of Formula III to obtain a compound of Formula IV; and
d) isolating the compound of Formula IV.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula IV, comprising:
a) reacting a compound of Formula I with a phosgene or its derivative and a suitable base in a suitable solvent to obtain a solution containing compound of Formula II,
b) adding a source of monomethyl amine to the solution of step a) to obtain a containing compound of Formula III,
c) adding a source of chloride to the solution of step b) to obtain a solution of containing compound of Formula IV,
d) adding water and a suitable acid to the step c) solution,
e) separating the organic and aqueous layers,
f) adding a suitable base to the aqueous layer, and
g) filtering the compound of Formula IV.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula IV having less than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11, comprising:
a) reacting a compound of Formula III with a source of chloride to obtain a solution containing compound of Formula IV having more than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11,
b) adding water and a suitable acid to the step a) solution,
c) separating the organic and aqueous layers,
d) adding a suitable base to the aqueous layer, and
e) filtering the compound of Formula IV.

In accordance with another embodiment, the present invention provides an improved process for preparation of chlorantraniliprole, comprising:

Chlorantraniliprole

a) preparing a compound of Formula IV according processes described as above embodiments, and
b) converting the compound of Formula IV in to chlorantraniliprole.

In accordance with another embodiment, the present invention provides a compound of Formula IV having less than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11.

In accordance with another embodiment, the present invention provides a composition comprising chlorantraniliprole, prepared by the process of the present invention and/or at least one excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses an improved process for the preparation of compound of Formula IV with high product yield and quality, wherein the improvements involve use of one-pot process without isolating intermediate compounds of Formula II and Formula III in a single solvent system and avoids explosives reagents, multiple solvent systems and cumbersome isolations such as time consuming solvent workups, drying and necessity of analyzing the compounds at each stage.

In accordance with one embodiment, the present invention provides an improved process for preparation of compound of Formula IV, comprising:

Formula IV

a) reacting a compound of Formula I with a phosgene or its derivative and a suitable base in a suitable solvent to obtain a compound of Formula II,

Formula I Formula II

b) reacting the compound of Formula II with a source of monomethyl amine to obtain a compound of Formula III, and

Formula III

c) reacting the compound of Formula III with a source of chloride to obtain a compound of Formula IV; wherein the step a) to c) are carried out in one-pot reaction without isolating the intermediate compound of Formula II and Formula III as solid.

The term "one-pot" as used in this application means a process uses a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one solvent/reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds can save time and resources, improves the efficiency of a chemical reaction, and offers better chemical yield.

The term RRT (relative retention time) as used in this application means in high pressure liquid chromatography (HPLC) the amount of time it takes for the compound to pass through the column is the retention time (RT) and comparison of the RT of one compound to another is called relative retention time (RRT).

The phosgene or its derivative as used in the aforementioned step a) is selected from phosgene as in gaseous form or as in liquid form consisting of but not limited tophosgene, diphosgene, triphosgene, bromophosgene and the like; preferably triphosgene.

The suitable base used in aforementioned step a) is selected from the group consisting of but not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group comprising of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, 2-picoline, 3-picoline and the like and mixtures thereof; preferably an inorganic base such as sodium carbonate, sodium bicarbonate or potassium bicarbonate; more preferably sodium bicarbonate.

The suitable solvent used in aforementioned step a) is selected from the group consisting of but not limited to amides, esters, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and the like and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; esters include, but are not limited to ethyl acetate, methyl acetate and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably ethyl acetate, acetonitrile or methylene chloride; more preferably methylene chloride.

The reaction of Formula I with a compound of Formula II is carried out at a temperature of about 0°C to reflux temperature; preferably at about 20°C to about 40°C.

After completion of the step a) reaction, the step a) solution advantageously processed to next step by adding a source of monomethylamine to the step a) solution without isolating the compound of Formula II as a solid.

The source of monomethylamine used in aforementioned step b) is selected from the group consisting of aqueous methyl amine, methyl amine in solvent, methyl amine gas and the like; preferably aqueous methyl amine or methyl amine gas.

Optionally the step b) is carried out in presence of a suitable acid, a suitable base or, a suitable second solvent. The suitable acid optionally used in aforementioned step b) is selected from the group consisting of acetic acid, formic acid, methanoic acid and the like. The suitable base optionally used in aforementioned step b) is selected from the group consisting of but not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group comprising of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine, 2-picoline, 3-picoline and the like and mixtures thereof. The suitable second solvent optionally used in aforementioned step b) is same as the solvent used in step a) of the aforesaid process.

The reaction of a Formula II with a source of monomethylamine is carried out at a temperature of about 25°C to reflux temperature; preferably at about 30°C to about 45°C.

After completion of the step b) reaction, the step b) solution advantageously processed to next step by adding a source of chloride to the compound of Formula III without isolating the compound of Formula III as a solid.

Optionally, after completion of the step b) reaction, the step b) solution may be washed with water to remove inorganic salts if any and then the resultant organic layer may be processed to next step by adding a source of chloride without isolating the compound of Formula III as a solid.

The source of chloride used in aforementioned step c) is selected from the group consisting of but not limited to sulfuryl chloride, N-chlorosuccinimide, chlorine gas, metal chloride-H2O2 in acid aqueous medium, HCl-H2O2, m-chloroperbenzoic acid/HCl, acetyl chloride and the like; preferably sulfuryl chloride.

Optionally the step c) is carried out in presence of a suitable solvent. The suitable solvent optionally used in aforementioned step c) is same as the solvent used in step a) of the aforesaid process.

The reaction of a Formula III with a source of chloride is carried out at a temperature of about 25°C to reflux temperature; preferably at about 30°C to about 45°C.

Generally chlorination reactions are prone to form impurities which are may be due to the reactions at other positional or side reactions with the amine moiety present in the substrate. These impurities may be identified by HPLCat RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11in the range of about 2 % toabout5 % respectively along with the required compound of Formula IV. Without control of these impurities at this stage the same may be carrying forwarded to subsequent stages and to final stage and at final stage one or more additional purification steps required to remove these impurities. Hence, the compound of Formula IV purity is important for preparation of pure chlorantraniliprole.

In contrast, the present invention advantageously separated these impurities by simply formation of salt of the resultant compound of Formula IV after chlorination reaction and separates the salt of compound of Formula IV as an aqueous layer and unwanted impurities by an organic layer.

In another embodiment, after completion of the chlorination reaction water may be added to the reaction mass and followed by adding a suitable acid to form a salt of compound of formula IV in heterogeneous solvent mixture and both organic and aqueous layers may be separated. Then after separating the impurities containing organic layer the resultant compound of Formula IV can be isolated from the aqueous layer by known methods, for example, adjusting pH of the aqueous layers to above 7 with a suitable base. Then the compound of Formula IV can be isolated from reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably by filtering the solids.

The suitable acid used herein for making salt formation is selected from hydrochloric acid, sulfuric acid, acetic acid, p-toluene sulfonic acid and the like and mixture thereof; preferably hydrochloric acid and suitable base used herein for neutralization is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide and the like and mixture thereof.

The resultant product may optionally be further dried at a temperature of about 30°C to about 80°C. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like.

The present invention provides compound of Formula IV prepared by the processes described as above having a purity of at least about 98%by HPLC, preferably at about 99.5% and having less than 0.5% by HPLC, preferably less than 0.2% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11.

In another embodiment, the present invention provides a compound of Formula IV having less than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11.
In another embodiment, the present invention provides an improved process for the preparation of chlorantraniliprole or a salt thereof, comprising preparing the compound of Formula IV as process described above, and converting the compound of Formula IV in to chlorantraniliprole or a salt thereof by any process known in the art for example WO2006/062978 or by the process described in the present specification.

In another embodiment, the present invention provides a composition comprising chlorantraniliprole, prepared by the process of the present invention and/or at least one excipient.

The present invention provides chlorantraniliprole and its intermediates, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:

Column Zorbax RX-C8
Mobile phase Mobile phase-A: Buffer and Acetonitrile
Mobile phase-B: Acetonitrile and water
Flow rate 1.0 mL/min
Elution Gradient
Detection 260 nm
Injection volume 20µL
Run time 75 min
Mode Time in min Mobile phase A
(% v/v) Mobile phase B (% v/v)
0 85 20
40 40 80
50 85 20

EXAMPLES

The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1:

Preparation of compound of Formula IV

Thiophosgene solution (78.5 gm) and700 mL methylene chloride was were added in to a round bottom flask at room temperature and stir for 10 min at 10°C to 20°C. To the solution was added compound of Formula I (100 gm),sodium bicarbonate (138.9 gm)and stir for 10-20 min at same temperature. Reaction mass was heated 25-35°C and stir for 6 hrs at same temperature. After completion of the reaction, to the reaction mass was added 40% aqueous monomethylamine (154 gm) at 10-20°C and stir for 3 hrs at 25-35°C. After completion of the reaction, to the reaction mass was added water (700 mL) and product containing organic layer was separated. To the product containing organic layer sulfuryl chloride (133.6 gm) was added slowly at 10-20°C and stir for 6hrs at 25-35°C. After completion of the reaction, to the reaction mass was added water (500 mL) and hydrochloric acid (150 mL) at 10-20°C and stir for 20 min at 25-35°C. Aqueous and organic layers were separated and product containing aqueous layer pH was adjusted to 8.0-9.0 with aq sodium hydroxide solution at 25°C to 35°C and stir for 30 min at same temperature. Filtered the solids and washed the wet cake with water (100 mL) and dry the wet material initially at 25-35°C for 60 min, then dry at 60-75°C for 6 hr to obtain title compound. Wt: 106 gm; Yield: 79%; HPLC Purity: 99.5%;

The organic layer was taken and concentrated completely under vacuum to obtain a residue and analyzed the residue by HPLC and the results are as follows:

Impurity at RRT Compound of Formula IV Residue from Organic layer
0.31 0.05% 2.82%
0.53 Nil 4.12%
0.79 0.1% 1.89%
0.89 Nil 1.52%
1.06 Nil 4.59%
1.84 Nil 3.28%
2.01 Nil 3.42%
2.03 Nil 2.35%
2.62 Nil 3.03%
2.96 Nil 1.90%
3.08 Nil 1.81%
3.11 Nil 4.72%

EXAMPLE-2:

Preparation of compound of Formula IV

Compound of Formula I (100 gm), methylene chloride (500 mL), sodium bicarbonate (138.9 gm) were added in to a round bottom flask and allowed to cool to 0-10°C and stir for 10-20 min at same temperature. To the reaction mass was added triphosgene solution (78.5 gm dissolved in 200 mL methylene chloride) at 0-10°C. Reaction mass was heated 25-35°C and stir for 6 hrs at same temperature. After completion of the reaction, to the reaction mass was added acetic acid (7.9 gm) and 40% aqueous monomethylamine (102.7 gm) at 25-35°C and stir for 3 hrs at same temperature. After completion of the reaction, to the reaction mass water (100 mL) was added and product containing organic layer was separated. To the product containing organic layer Sulfuryl chloride (134.1 gm) was added slowly at 25-35°C and stir for 3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 0-5°C and was added water (500 mL) at same temperature. pH of the reaction mass was adjusted to 9.5 with aq sodium hydroxide solution at -5°C to 5°C and stir for 30 min at same temperature. Then the product containing organic layer was separated and aqueous layer was extracted with methylene chloride (200 mL). The combined organic layer was concentrated under vacuum at below 40°C to get semi solid. To the solids was added a mixture of methanol (50 mL) and water (450 mL) at 25-35°C and stir for 3 hrs at same temperature. Filtered the solids and washed the wet cake with water (100 mL) and dry the wet material initially at 25-35°C for 60 min, then dry at 60-75°C for 6 hr to obtain title compound. Wt: 105gm; Yield: 78.3%.

EXAMPLE-3:

Preparation of Chlorantraniliprole

3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid ethyl ester (100 gm) and tetrahydrofuran (500 mL) were added in to a round bottom flask at about 25°C to about 30°C. To the reaction mass was added compound of Formula IV (60.1 gm) at about 25°C to about 30°C. Then reaction mass was cool to about -40°C to about -50°C and was added 1M LiHMDS in tetrahydrofuran (906 mL) at same temperature and stir for 1 hr at same temperature. After completion of the reaction, to the reaction mass was charged water (1 lit) and ethyl acetate (1 lit) at about -40°C to about -50°C. Reaction mass temperature was heated to 25-30°C and separated the organic and aqueous layers. Organic layer was concentrated under vacuum at 40-45°C to obtain a solid. Then the obtained solid was mixed with acetonitrile (500 mL) at 25-30°C. To the reaction mass was added water (250 mL) at 25-30°C and stir for 1 hr at same temperature. Precipitated solid was filtered and washed with water (100 mL), acetonitrile (50 mL) and dried the wet material under vacuum at 50-60°C to obtain title compound. Wt: 100 gm.

REFERENCE EXAMPLE-1:

Preparation of compound of Formula II

Compound of Formula I (100 gm) and methylene chloride (500 mL) were added in to a round bottom flask and allowed to cool to 0-10°C. To the reaction mass was slowly added pyridine (104.4 gm) and triphosgene (68.7 gm dissolved in 100 mL methylene chloride) at 0-10°C and stir for 2 hrs at same temperature. Reaction mass was heated 25-35°C and stir for 6 hrs at same temperature. After completion of the reaction, to the reaction mass was added water (100 mL), cool to 10°C and stir for 3 hrs at same temperature. Precipitated solids were filtered and washed with water (100 mL) and dry the wet material initially at 30-35°C for 60 min, then dry at 60-75°C for 6 hr to obtain title compound. Wt: 105 gm.

REFERENCE EXAMPLE-2:

Preparation of compound of Formula III

Compound of Formula II (100 gm), acetic acid (5.8 mL) and methylene chloride (425 mL) were added in to a round bottom flask and heated to 30-35°C. To the reaction mass was added 40% aq methylamine solution (58 gm) and stir for 3 hrs at 30-35°C. After completion of the reaction, to the reaction mass was added water (85 mL) and extracted product in to methylene chloride (85 mL). Combined organic layer was concentrated under vacuum at below 55°C and dry the wet material initially at 45-50°C to obtain title compound. Wt: 83 gm.

REFERENCE EXAMPLE-3:

Preparation of compound of Formula IV

Compound of Formula III (80 gm), methylene chloride (340 mL) and Sulfuryl chloride (61.5 gm) were added in to a round bottom flask at 30-35°C and stir for 3 hrs at same temperature. After completion of the reaction, to the reaction mass was added water (70 mL) and pH adjusted to 8.5 to 9.5 with lye solution at -5°C to 5°C and stir for 30 min at same temperature. Then the product containing organic layer was separated and was concentrated under vacuum at below 40°C to get semi solid. To the solids was added a mixture of methanol (35 mL) and water (300 mL) at 25-35°C and stir for 3 hrs at same temperature. Filtered the solids and washed the wet cake with water (70 mL) and dry the wet material initially at 25-35°C for 60 min, then dry at 60-75°C for 6 hr to obtain title compound. Wt: 78 gm.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We Claim:

1. An improved process for preparation of compound of Formula IV, comprising:

Formula IV
a) reacting a compound of Formula I with a phosgene or its derivative and a suitable base in a suitable solvent to obtain a compound of Formula II,

Formula I Formula II
b) reacting the compound of Formula II with a source of monomethyl amine to obtain a compound of Formula III, and

Formula III
c) reacting the compound of Formula III with a source of chloride to obtain a compound of Formula IV; wherein the step a) to c) are carried out in one-pot reaction without isolating the intermediate compound of Formula II and Formula III as solid.

2. The process as claimed in claim 1, wherein in the phosgene or its derivative is selected from the group consisting of phosgene, diphosgene, triphosgene and bromophosgene.

3. The process as claimed in claim 1, wherein in the suitable base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, 2-picoline, 3-picoline and mixtures thereof.

4. The process as claimed in claim 1, wherein in the suitable solvent is selected from the group consisting of dimethylacetamide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixture thereof.

5. The process as claimed in claim 1, wherein in the source of monomethyl amine is selected from the group consisting of aqueous methyl amine, methyl amine in solvent and methyl amine gas.

6. The process as claimed in claim 1, wherein in the source of chloride is selected from the group consisting of sulfuryl chloride, N-chlorosuccinimide, chlorine gas, metal chloride-H2O2 in acid aqueous medium, HCl-H2O2, m-chloroperbenzoic acid/HCl and acetyl chloride.

7. The process as claimed in claim 1, wherein in the phosgene or its derivative is triphosgene, the base is sodium carbonate, sodium bicarbonate or potassium bicarbonate; the solvent is ethyl acetate, acetonitrile or methylene chloride; the source of chlorideissulfuryl chloride; and the source of monomethyl amine is aqueous methyl amine or methyl amine gas.

8. An improved process for preparation of compound of Formula IV having less than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11, comprising:
a) reacting a compound of Formula III with a source of chloride to obtain a solution containing compound of Formula IV having more than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11,
b) adding water and a suitable acid to the step a) solution,
c) separating the organic and aqueous layers,
d) adding a suitable base to the aqueous layer, and
e) filtering the compound of Formula IV.

9. The process as claimed in claim 8, wherein in the source of chloride is selected from the group consisting of sulfuryl chloride, N-chlorosuccinimide, chlorine gas, metal chloride-H2O2 in acid aqueous medium, HCl-H2O2, m-chloroperbenzoic acid/HCl and acetyl chloride; wherein the suitable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, p-toluene sulfonic acid and mixture thereof; and wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, caesium hydroxide, lithium hydroxide and mixture thereof.

10. A compound of Formula IV having less than 0.5% by HPLC of at least one of impurities at RRT-0.31, RRT-0.53, RRT-0.79, RRT-0.89, RRT-1.06, RRT-1.84, RRT-2.01, RRT-2.03, RRT-2.62, RRT-2.96, RRT-3.08 and RRT-3.11.