DESC:Field of the Invention
The present invention relates to an improved process for the preparation of advanced intermediate of Formula-I of Chlorantraniliprole. And also relates to an economically viable process for key starting material of Formula-II.

Background of the Invention
Anthranilamide derivatives are a kind of novel insecticides with high efficacy and safety. 3-Bromo-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide is highly effective against insects, which is commercialized by DuPont, its generic common name is Chlorantraniliprole.

There are a number of methods reported for preparing phenylcarboxamide of formula-I, for example:

WO 2006062978 A1 discloses a process for the preparation of 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I by chlorinating the 2-amino-3-methylbenzoic acid of Formula-II in the presence of N-chlorosuccinimide in DMF solvent to produce 2-amino-5-chloro-3-methylbenzoic acid of Formula-III, which undergoes further esterification in the presence of dimethylsulfate and DBU in acetonitrile solvent to obtain methyl 2-amino-5-chloro-3-methylbenzoate of Formula-IV. Further, compound of Formula-V is reacted with methylamine in acetonitrile solvent to obtain 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I. The synthetic scheme is depicted in below Scheme-I.
Scheme-I

The process disclosed in WO 2006/062978 A1 suffers from the following disadvantages outlined below:
1. Isolation of chlorinated compound in step-I involves uses of ether solvent which is expensive and cannot be used in plant scale. Yield of the chloro compound is only 75.4%.
2. Esterification of step-II compound involves usage of expensive reagent 1,4-diazabicyclo[5.4.0]undec-7-ene (DBU). Both DBU and dimethyl sulphate were added in three lots for reaction completion. Isolation process of ester compound is laborious.
3. The final step-III amidation involves usage of mixed solvents like acetonitrile and ethylene glycol which makes it difficult to recover and reuse.

Different experimental procedures have been reported in the literature for the preparation of key starting material, 2-amino-3-methylbenzoic acid of Formula-II.

Bruce Guise (Journal of the Chemical Society Perkin Transactions 1, Organic and Bio-Organic Chemistry (1972-1999), (8), 1637 -1648; 1982) discloses a process for the preparation of 2-amino-3-methylbenzoic acid of Formula-II by reducing the 3-methyl-2-nitrobenzoic acid of Formula-V in the presence of Raney nickel catalyst and hydrazine hydrate in ethanol as solvent. Yield of the product is 66% by theory. The synthetic procedure is depicted in below Scheme-II:

SCHEME-II
The process disclosed in Journal of the Chemical Society, Perkin Transactions 1, Organic and Bio-Organic Chemistry (1972-1999), (8), 1637 -1648; 1982 suffers from the following disadvantages outlined below:
1. Raney Nickel was used in three lots in the process and quantity of Raney Nickel was not mentioned.
2. No recovery and reuse of the catalyst and reagent were mentioned.
3. Yield of the product is moderate (66.0%).

Kano (Bulletin of the Chemical Society of Japan, 1987, 60(10), 3659-62) discloses a process for the preparation of 2-amino-3-methylbenzoic acid of Formula-II by reduction of 3-methyl-2-nitrobenzoic acid of Formula-V in the presence of HCl and Tin (Sn) catalyst in aqueous ethanol solvent followed by addition of ammonia. Yield of the isolated product is 89%.
The synthetic procedure is depicted in below Scheme-III:

SCHEME-III
The process disclosed in Bulletin of the Chemical Society of Japan, 1987, 60(10), 3659-62 has the following disadvantages outlined below:
? Although yield is high the process suffers by generating lot of sludge which leads to tedious work-up process to isolate the product. It is time consuming and lot of effluent will be generated at plant scale.
Further, Jian-Feng (Journal of Organic Chemistry, 2003, 68(23), 8918-8931), discloses a process for the preparation of 2-amino-3-methylbenzoic acid of Formula-II by catalytic reduction of 3-methyl-2-nitrobenzoic acid of Formula-V in the presence of palladium carbon in ethanol used as solvent medium. Yield of the product is 99% by theory. The synthetic procedure is depicted in Scheme-IV as below:

SCHEME-IV

The following are the disadvantages of the process disclosed in Journal of Organic Chemistry, 2003, 68(23), 8918-8931.
? Highly expensive palladium/carbon catalyst is used in the process which is not viable on commercial scale.
? Also requires hydrogen pressure condition.
Jeon (Jingxi Huagong Zhongjianti, 2010, 40(5), 17-19) discloses a process for the preparation of 2-amino-3-methylbenzoic acid of Formula-II by reducing the 3-methyl-2-nitrobenzoic acid of Formula-V in the presence of FeCl3 6H2O/carbon/ NaOH in H2O solvent followed by addition of hydrazine hydrate. The synthetic procedure is depicted in below Scheme-V:

SCHEME-V
The process disclosed in Jingxi Huagong Zhongjianti, 2010, 40(5), 17-19 has the following disadvantages outlined below:
? The process suffers by generating lot of sludge which leads to tedious work-up process to isolate the product. It is time consuming and lot of effluent will be generated at plant scale. Yield and quality of the product is not given.

Objective of the Invention
The main objective of the present invention is to provide a simple and cost effective and commercially viable processes for the preparation of advanced intermediate, 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I for Chlorantraniliprole and its key starting material, 2-amino-3-methylbenzoic acid of Formula-II.

Summary of the Invention:
The present invention provides a process for preparation of 2-amino-5-chloro-3,N-dimethyl benzamide of Formula-I, comprising the steps of:
a) reducing the 3-methyl-2-nitrobenzoic acid of Formula-V

Formula-V
with Raney nickel catalyst and hydrazine hydrate in the presence of aqueous base followed by neutralization with an acid to produce compound of Formula-II.

Formula-II
b) chlorinating the compound of Formula-II obtained in step a) with N-chlorosuccinimide in a suitable solvent to produce compound of Formula-III.

Formula-III
c) esterifying the compound of Formula-III with dimethyl sulphate in the presence of an inorganic base in a suitable solvent to produce compound of Formula-IV;

Formula-IV
d) reacting the compound of Formula-IV with methylamine in presence of a base in a suitable solvent to produce compound of Formula-I.

Formula-I

Detailed Description of the Invention
The present invention provides a process for preparation of 2-amino-5-chloro-3,N-dimethyl benzamide of Formula-I, comprising the steps of:
a) reducing the 3-methyl-2-nitro benzoic acid of Formula-V with Raney nickel catalyst and hydrazine hydrate in the presence of aqueous base to produce compound of Formula-II,
b) chlorinating the compound of Formula-II obtained in step a) with N-chlorosuccinimide in a suitable solvent to produce compound of Formula-III,
c) esterifying the compound of Formula-III with dimethyl sulphate in the presence of inorganic base in suitable solvent to produce compound of Formula-IV,
d) reacting the compound of Formula-IV with methylamine in presence of base in a suitable solvent to produce compound of Formula-I.
In step a) of present invention, base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide.

In step (a) of the present invention, the reaction may be performed usually from 20°C to 100 oC for 1 to 5 hours, preferably 30-65°C for 1 to 2 hours. The obtained compound of Formula-II may be isolated by filtration of Raney Nickel catalyst, neutralization of reaction mass with an acid, and filtration or used in the next reaction directly or optionally after further purification.

In step (a) of the present invention, yield of the product is 90-95% with purity by HPLC >98.0%.

Raney-Nickel is recycled by adding fresh lot of reactants to the same catalyst.

In step (b) of the present invention, the suitable solvent is selected from acetonitrile, N,N-dimethylformamide, chloroform, dimethylsulphoxide, etc., preferably N,N-dimethylformamide.

In step (b) of the present invention, the reaction may be performed usually from 20°C to 100oC for 1-10 hours, preferably 40-45°C for 1-2 hours.

Compound of Formula-III in step-b) is isolated by quenching the reaction mass into water. Yield of the compound is > 90.0% with purity by HPLC > 98.0%.

Further, from the filtrate N-chlorosuccinimide is recovered by passing chlorine gas. Recovered N-chlorosuccinimide is reused for same chlorination purpose.

In step (c) of the present invention, base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate preferably potassium carbonate.

In step (c) of the present invention, suitable solvent is selected from acetone, methyl ethyl ketone, diethyl ketone or mixture thereof preferably acetone.

In step (c) of the present invention, the reaction may be performed usually from 20°C to boiling point of the solvent used for 1-10 hours, preferably 25-35°C for 1-2 hours. The compound of Formula-IV from step (c) is isolated by quenching the reaction mass into water in > 90.0% yield.

Further, acetone is recovered from the filtrate. Recovered acetone is reused in step (c).

The base used in step d) of present invention is selected from alkoxides such as sodium methoxide, sodium ethoxide, potassium-tert-butoxide and sodium-tert-butoxide etc., preferably sodium methoxide.

The suitable solvent used in step d) of present invention comprising of alcohol is selected from methanol, ethanol, n-propanaol, isopropanol, n-butanol or mixture thereof.

In step (d) of the present invention, the reaction may be performed usually from 20°C to boiling point of the solvent used for 2 to 24 hours, preferably 60-65°C for 10-15 hours. The compound of Formula-I from step (d) is isolated from reaction mass by distillation of solvent followed by quenching into water in >85% yield with purity > 97.0% by HPLC.

Further, compound of Formula-I is reacted with 3-bromo-1(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid in the presence of thionyl chloride in toluene or acetonitrile or mixture thereof to produce Chlorantraniliprole.

Advantages of present invention:
1. Process for the preparation of 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I, the advanced intermediate of Chlorantraniliprole is highly cost effective and commercially viable process.
2. In each stage, the corresponding intermediates are isolated from water.
3. In each stage, yield of the product is about 90.0% by theory.
4. Catalysts, reagents and solvents are recycled and reused in the process.
5. Raney-Nickel is recycled by adding fresh lot of reactants to the same catalyst.
6. N-Chlorosuccinimide is regenerated in step (b) from the mother liquor by purging chlorine gas and reused.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES:
EXAMPLE-01: Preparation of 2-Amino-3-methylbenzoic acid of Formula-II
Aq. NaOH solution (600 ml, prepared from 33.1g sodium hydroxide and 600 ml of DM water, 0.825 moles), 3-methyl-2-nitro benzoic acid of Formula-V (100.0g, 0.552 moles) were charged into 3.0 lit 4 necked RB flask. Reaction mass was stirred for 10 min at 25-350C to get clear solution. Raney Ni (10.5g) was added to the above reaction mass and temperature was raised to 60-650C. Aq. solution of Hydrazine hydrate (dilute 53.14 g of Hydrazine hydrate (80.0% w/v) with 53.0 ml of DM.Water, 0.828 moles) was added to the reaction mass during 45-60 min. Reaction mass was stirred for 1 hour at 60-650C. After reaction completion, reaction mass was cooled to 25-350C and settle for 30 min. Reaction mass was filtered and pH of the filtrate was adjusted to 5.0-5.5 with diluted aq. hydrochloric acid to get pale brown coloured suspension. The resulting suspension was stirred for 1h at 25-35°C and solid was filtered under suction. Material was dried in hot air oven at 70-750C for 10-12 hours. Weight of the compound: 79.0 g (94.7% by theory). Purity by HPLC: 99.0%.

EXAMPLE-02: Preparation of 2-Amino-3-methylbenzoic acid of Formula-II by reverse addition of the reagents.
DM water (200 ml) and Raney Ni (2.0g) were charged into 3.0 lit 4 necked RB flask. Reaction mass was stirred for 10 min at 25-350C. In another RB flask, aq. NaOH solution (Prepared from 33.1g sodium hydroxide and 400 ml of DM water, 0.825 moles), 3-methyl-2-nitro benzoic acid of Formula-V (100.0g, 0.552 moles) and hydrazine hydrate (53.14 g of Hydrazine hydrate (80.0% w/v) were charged and prepared a solution and added this solution to above Raney Ni mass at 40-450C during 60 min to 90 min. After completion of addition, reaction mass was stirred for 1 h at 40-450C to complete the reaction. After reaction completion, reaction mass was cooled to 25-350C and filtered. pH of the filtrate was adjusted to 5.0-5.5 with diluted aq. hydrochloric acid to get pale brown coloured suspension. The resulting suspension was stirred for 3h at 25-35°C and solid was filtered under suction and washed with water. Material was dried in hot air oven at 70-750C for 10-12 hours. Weight of the compound: 79.0 g (94.7% by theory). Purity by HPLC: 99.0%.

EXAMPLE-03: Preparation of 2-Amino-4-chloro-3-methylbenzoic acid of Formula-III.
2-Amino-3-methylbenzoic acid of Formula-II (70.0g, 0.463 moles) and N,N-dimethylformamide (210.0 ml) were charged into 500.0 ml 4 necked RB flask. Reaction mass was stirred for at 25-350C. N-chlorosuccinimide (64.9 g, 0.486 moles) was added in lots to the reaction mass by maintaining the reaction mass temperature not crossing 35°C. Reaction mass temperature was raised to 40-450C and stirred for 2 hours. After completion of reaction, reaction mass was slowly added to chilled water (630.0 ml) and stirred for 1hour at 20-250C. Solid was filtered under suction and washed with DM.Water (420.0 ml). Compound was suck dried for 60 min. Then dried in hot air oven at 70-750C for 6 hours. Weight of the title compound: 78.8 g (% of yield by theory: 91.90 %). Purity by HPLC: 98.0%.

EXAMPLE-04: Preparation of 2-Amino-4-chloro-3-methylbenzoic acid of Formula-III using chloroform during isolation of compound.
2-Amino-3-methylbenzoic acid of Formula-II (70.0g, 0.463 moles) and N,N-dimethylformamide (210.0 ml) were charged into 500.0 ml 4 necked RB flask. Reaction mass was stirred for at 25-350C. Reaction temperature was raised to 40-450C and N-chlorosuccinimide (64.9 g, 0.486 moles) was added in lots to the reaction mass by maintaining the reaction mass temperature 40-450C. After completion of addition, maintained the reaction mass for 2 h at 40-450C. After completion of reaction, reaction mass was cooled to 25-300C and slowly added to chloroform (1050.0 ml). Then reaction mass was cooled to 0-50C. After 2 h maintenance, solid was filtered under suction and washed with chloroform (420.0 ml). Compound was suck dried for 60 min. Wet weight of the material is 122.5 g. The resulting wet material and DM.Water (280.0 ml) were charged into another RB Flask and stirred for 1 h at 25-350C. Solid was filtered off and washed with DM.Water (70.0 ml). Compound was suck dried for 60 min. Then material was dried in hot air oven at 70-750C for 6 hours. Weight of the title compound: 79.0 g (% of yield by theory: 91.90 %). Purity by HPLC > 98.0%.

Filtrate from water leachings were kept aside for recovery of N-chlorosuccinimide.

EXAMPLE-05: Preparation of Methyl 2-amino-4-chloro-3-methylbenzoate of Formula-IV.
2-Amino-4-chloro-3-methylbenzoic acid of Formula-III (70.0g, 0.377 moles) and acetone (700.0 ml) were charged into 2.0 L 4 necked RB flask. Reaction mass was stirred for 5-10min at 25-350C. Potassium carbonate (41.65g, 0.3016 moles) was added to the above reaction mass during 5-10 min at 25-350C. Dimethyl sulphate (52.36g, 0.415 moles) was added during 30 min by maintaining the reaction mass temperature not crossing 35°C. Reaction mass was stirred for 2 hours at 25-350C. After completion of reaction, salts were filtered off under suction and washed with Acetone (140.0 ml). Solvent from the filtrate was completely distilled off under vacuum at 500C of bath temperature to obtain brown colored oily crude. DM water (350.0 ml) was added to the resulting oily crude and stirred for 1 hour at 10-150C. Solid was filtered off under suction and washed with DM.Water (140.0 ml). Material was suck dried for 60 min then dried in oven at 25-350C for 6 hours. Weight of the product: 68.5g (% of yield by theory: 91.0%). Purity by HPLC: 92.0%

EXAMPLE-06: Preparation of Methyl 2-amino-5-chloro-3,N-dimethyl benzamide of Formula-I.
Methyl 2-amino-4-chloro-3-methylbenzoate of Formula-IV (60.0g, 0.30 moles) and monomethylamine in methanol (25.0% w/v, 375.0 g, 3.0 moles) were charged into 1.0 L 4 necked RB flask. Reaction mass was stirred for 5-10 min at 25-350C. Sodium methoxide (24.1% w/w) solution in methanol (13.48g, 0.06 moles) was added to the reaction mass and stirred for 10 min. Reaction mass was heated to 60-650C and maintained for 11 hours. After reaction completion, reaction mass was cooled to 50-550C and activated carbon (12.0g) was added to the reaction mass and stirred for 30 min. Reaction mass was filtered through hy-flow bed under suction and washed with methanol (120.0 ml). Solvent from the filtrate was distilled off completely under vacuum at 600C of bath temperature to obtain pale brown colored solid. DM water (600.0 ml) was added to the crude and stirred for 1 hour at 25-350C. Solid was filtered under suction and washed with DM water (120.0 ml). Compound was suck dried for 60 min then dried in vacuum oven at 75-800C for 6 hours. Weight of the product: 52.16 g. (% of yield by theory: 87.37%). Purity by HPLC: 97.0%.

EXAMPLE-07: Preparation of Methyl 2-amino-5-chloro-3,N-dimethyl benzamide of Formula-I using monomethylamine gas.
Methanol (120 ml) was charged into the 1.0 L 4 necked RB flask and cooled to 0-50C and monomethylamine gas (27.9 g, 0.9 moles) was purged into the methanol. After completion of gas purging, reaction mass was allowed to 25-300C and charge the methyl 2-amino-4-chloro-3-methylbenzoate of Formula-IV (60.0g, 0.30 moles) into the mass. Reaction mass was stirred for 5-10 min at 25-350C. Sodium methoxide (24.1% w/w) solution in methanol (13.48g, 0.06 moles) was added to the reaction mass and stirred for 10 min. Reaction mass was heated to 50-550C and maintained for 10 hours. After reaction completion, distilled off methanol (60 ml) from reaction mass under vacuum. Then water (240 ml) was added to the reaction mass at 50-55°C and stirred for 30 min. Reaction mass was cooled to 10-150C, and stirred for 1h and solid was filtered off and washed with 20% aq. methanol (60 ml). Product was suck dried for 60 min then dried in hot air oven at 60-650C for 10-12 hours. Weight of the product: 56.0 g. (% of yield by theory: 93.6%). Purity by HPLC: 97.96%.

EXAMPLE-08: Preparation of Chlorantraniliprole.
Toluene (75.0 ml) and 3-Bromo-1(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (25.0g, 0.0826 moles) were charged into the 250 ml 4 necked RB flask (Reactor-1). Reaction mass was stirred for 5-10 min at 25-350C. Thionyl chloride (11.78 g, 0.099 moles) was added to the above reaction mass slowly through addition funnel during 10-15 min by maintaining the mass temperature not crossing 350C. After completion of addition, reaction mass was heated to 75-800C and stirred for 3.5 hours. After completion of reaction, mass was cooled to 25-35°C and kept aside under nitrogen atmosphere (Reaction mass-1). Reaction mass-1 is pale brown colour clear solution.

2-Amino-5-chloro-3,N-dimethylbenzamide of Formula-I (17.25g, 0.0867 moles) and Acetonitrile (50.0 ml) were charged in another 250 ml 4 necked RB flask (Reactor-2), and stirred for 5-10 min at 25-350C. 3-Picoline (19.95g, 0.215 moles) was added to the above reaction mass and stir for 5-10 min. Reaction mass-1 was added dropwise to the above reaction mass during 20-30 min by maintaining the mass temperature not crossing 350C. And then reaction mass was stirred for 3.5 hours at 25-350C.
After completion of reaction, mass was quenched into DM water (75.0 ml) at 25-35°C and the resulting suspension was stirred for 1hour. Solid was filtered under suction with the help of toluene (25.0 ml). Solid was washed with aq. acetonitrile (75.0 ml, prepared from 56.0 ml acetonitrile and 19.0 ml of DM water) and suck dried for 1h. The resulting solid was leached with acetonitrile (50.0 ml) followed by DM water (100.0 ml) at 25-35°C. Product was dried in hot air oven at 75-800C for 4-5 hours. Weight of the product: 33.4g (% of yield by theory: 83.6). Purity of the compound by HPLC: 99.0%.

EXAMPLE-09: Preparation of Chlorantraniliprole using acetonitrile alone as solvent medium.
Acetonitrile (300.0 ml) and 3-bromo-1(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (100.0g, 0.330 moles) were charged into the 1.0L 4 necked RB flask (Reactor-1). Reaction mass was stirred for 5-10 min at 25-350C. Thionyl chloride (43.2g, 0.363 moles) was added to the above reaction mass slowly through addition funnel during 15-20 min by maintaining the mass temperature not crossing 350C. After completion of addition, reaction mass was heated to 75-800C and stirred for 3.5 hours. After completion of reaction, reaction mass was cooled to 25-35°C and kept aside under nitrogen atmosphere (Reaction mass-1). Reaction mass-1 is pale brown colour clear solution.

2-Amino-5-chloro-3,N-dimethylbenzamide of Formula-I (68.8g, 0.3464 moles) and Acetonitrile (200.0 ml) were charged in another 2.0L 4 necked RB flask (Reactor-2), and stirred for 5-10 min at 25-350C. 3-Picolne (36.9g, 0.396 moles) was added to the above reaction mass and stir for 5-10 min. Reaction mass-1 was added dropwise to the above reaction mass during 20-30 min by maintaining the mass temperature not crossing 350C. And then reaction mass was stirred for 3.5 hours at 25-350C.
After completion of reaction, reaction mass was cooled to 5-10oC and stirred for 2-2.5h. Solid was filtered under suction with the help of chilled acetonitrile (100.0 ml). Solid was suck dried for 30-45min. Product was dried in hot air oven at 75-800C for 6-8 hours. Weight of the product: 145.5g (% of yield by theory: 91.1). Purity of the compound by HPLC: 99.0%.
,CLAIMS:WE CLAIM:
1. A process for preparation of 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I,

comprising the steps of:
a) reducing the 3-methyl-2-nitrobenzoic acid of Formula-V

Formula-V
with Raney nickel catalyst and hydrazine hydrate in the presence of aqueous base to produce Formula-II,

Formula-II
b) chlorinating the compound of Formula-II obtained in step a) with N-chlorosuccinimide in suitable solvent to produce compound of Formula-III,

Formula-III

c) esterifying the compound of Formula-III with dimethyl sulphate in the presence of inorganic base in a suitable solvent to produce compound of Formula-IV,

Formula-IV
d) reacting the compound of Formula-IV with methylamine in presence of base in a suitable solvent to produce compound of Formula-I.

2. The process as claimed in claim 1, wherein the base used in step a) is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate.

3. The process as claimed in claim 1, wherein the suitable solvent used in step-b) is a polar aprotic solvent, which is selected from acetonitrile, N,N-dimethylformamide, chloroform, dimethylsulphoxide or mixture thereof.

4. The process as claimed in claim 1, wherein the inorganic base used in step c) is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate.

5. The process as claimed in claim 1, wherein the suitable solvent used in step c) is selected from acetone, methyl ethyl ketone, diethyl ketone or mixture thereof.

6. The process as claimed in claim 1, wherein the base used in step-d) is an alkoxide, which is selected from sodium methoxide, sodium ethoxide, potassium-tert-butoxide and sodium-tert-butoxide.

7. The process as claimed in claim 1, wherein the suitable solvent used in step-d) is selected from methanol, ethanol, n-propanaol, isopropanol or mixture thereof.
8. 2-Amino-5-chloro-3,N-dimethylbenzamide of Formula-I prepared by the process as claimed in claim-1 is used in the preparation of Chlorantraniliprole.